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Dev Cell. 2018 Jun 18;45(6):738-752.e6. doi: 10.1016/j.devcel.2018.05.021.

Competition between TIAM1 and Membranes Balances Endophilin A3 Activity in Cancer Metastasis.

Author information

1
Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
2
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
3
Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
4
Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Electronic address: eisenman@fredhutch.org.
5
Basic Sciences Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA. Electronic address: jbai@fredhutch.org.

Abstract

Normal cells acquire aggressive behavior by modifying signaling pathways. For instance, alteration of endocytosis profoundly impacts both proliferation and migration during tumorigenesis. Here we investigate the mechanisms that enable the endocytic machinery to coordinate these processes. We show that a membrane curvature-sensing protein, endophilin A3, promotes growth and migration of colon cancer cells through two competing mechanisms: an endocytosis pathway that is required for proliferation and a GTPase regulatory pathway that controls cell motility. EndoA3 stimulates cell migration by binding the Rac GEF TIAM1 leading to activation of small GTPases. Competing interactions of EndoA3 with membrane versus TIAM1 modulate hyperproliferative and metastatic phenotypes. Disruption of EndoA3-membrane interactions stimulates TIAM1 and small GTPases in vitro, and further promotes pro-metastatic phenotypes in vivo. Together, these results uncover a coupling mechanism, by which EndoA3 promotes growth and migration of colon cancers, by linking membrane dynamics to GTPase regulation.

KEYWORDS:

BAR domain; PTEN; Rac1; TIAM1; cell migration; endocytosis; endophilin; membrane remodeling; metastasis

PMID:
29920278
PMCID:
PMC6095642
[Available on 2019-06-18]
DOI:
10.1016/j.devcel.2018.05.021
[Indexed for MEDLINE]

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